It is known that there are numerous components in exhaled air that may provide useful insights into metabolic processes in certain diseases, as well as function as indicators of certain diseases and even indicating the presence of certain disease causing agents. The concentrations of such components have been studied in great detail in both research and clinical settings. Based on these insights, the concentration values aid in the establishing of a diagnosis, and have proven useful to monitor the well being of a patient, etc. Two examples of clinically interesting components in exhaled air are inorganic and organic gaseous compounds. Examples of gaseous compounds present in exhaled air include nitrogen monoxide, here nitric oxide (NO), carbon dioxide (CO2), oxygen (O2), and volatile organic compounds. Further examples are more or less complex chemical compounds and biomolecules that can be detected in exhaled breath condensate, such as hydrogen peroxide, S-nitrosothiols, nitrotyrosine, proteins, cytokines, and macromolecules, to mention only a few.
An important example is NO, which since it was found to be a diagnostic marker of inflammation in the early 1990-ies, has become the focus of much research. Different techniques and sensors have been suggested for use in the determination of NO concentration. Examples include, but are not limited to chemiluminescence, semiconductor-based sensors, electrochemical sensors, and polymer-based sensors.
The American Thorax Society (ATS) and the European Respiratory Society (ERS) have published guidelines for the standardized examination of the lung function and of the determination of lung-function markers (See for example “An Official ATS Clinical Practice Guideline: Interpretation of Exhaled Nitric Oxide Levels (FENO) for Clinical Applications”, in Am. J. Respir. Crit. Care Med. 2011, 184: 602-615).
The main emphasis of the ATS/ERS guidelines is the examination and demonstration of endogenous NO of the deeper lung areas in the exhaled air (exhalate). The guidelines indicate various standards in this regard for the various measuring methods such as the online or offline measuring of adults, but also of children.
One problem in the determination of NO in exhaled air is the fact that the fractionated, endogenous NO (FENO) that stems from the deeper-lying areas of the lung, is present in clearly lower concentrations than nasal NO, so that the measured values of FENO are offset by the admixture of nasal NO.
The ATS/ERS guidelines take this circumstance into account and stipulate making the patient exhale against an expiratory resistance of at least 5 cm H2O. The velum will be closed and the nasopharynx isolated when the patient exhales against such a resistance.
The ATS/ERS guidelines also take account of the fact that the concentration of FENO is heavily dependent on the expiratory flow, because the greater the expiratory flow is, the lower the measurable FENO concentrations in the exhaled air. Therefore, the guidelines stipulate in this regard that the patient be allowed to exhale at a constant exhalation rate of preferably 50 ml/s. To this end the patient is requested to independently maintain the exhalation rate constant at a given level with the aid of an optical display. Flow meters, pressure indicators and also computer-animated graphics serve as displays.
In addition, the ATS/ERS guidelines require that the measured values be recorded in the range of a NO plateau. However, since the NO plateau is adjusted only offset in time after the beginning of the exhalation, the patient must complete a constant exhalation over a period of 4 or 10 seconds, depending on the age of the patient. The standard methods stipulated by the ATS and the ERS are recommended for adults and children above the age of 6 years.
Collectors of samples of respiratory gas are known in the state of the art for online as well as for offline measuring.
One sample collector for the offline measuring of FENO, using which respiratory gas samples can be collected under the required ATS/ERS conditions, is disclosed in the ATS/ERS guidelines (2011). This collector consists of a guide tube with mouthpiece that comprises a NO filter on the inhalation side through which the patient inhales surrounding air. The exhalation takes place against an expiratory resistance generated by modification in the mouthpiece. The exhaled air is collected in a MYLAR® bag. In order to maintain the stipulated ATS/ERS standard, the sample collector is also equipped with a pressure indicator assisting the patient in executing the required breathing maneuver under self-control.
In another offline sample collector, also disclosed in the ATS/ERS guidelines, the exhaled air is fractionated in that at first the dead-space component from the upper lung areas is separated in a catch bag. The fraction from the lower lung areas is subsequently trapped in a second collection container and later supplied to the analysis.
US 2008/0221471 shows an apparatus for the collection of airway gases, including NO, from a subject comprising a first means for producing closure of the velum of the subject, and a second means for the collection of airway gases, wherein the first and second means need not be integrated with each other. It appears from the disclosure that said means for producing closure of the velum rely on the presence of an adjustable/changeable resistor optionally followed by a pressure gauge, and that the subject is instructed to try to keep a stable pressure corresponding to a desired flow during exhalation. The disclosure of US 2008/0221471 also discusses nasal NO-measurements, making it clear that also here the means for producing closure of the velum require the cooperation of the subject. Moreover, the nasal airways are isolated from the oral airways by the subject performing the Valsalva maneuver to consciously maintain a closed velum while a sample is aspirated through the nasal airways.
Another device is disclosed in CA 2 669 385, which shows a device for high flow therapy utilizing a non-sealing respiratory interface. This device concerns the delivery of therapeutic gases, mainly oxygen, and contains no mentioning of the possibility to close the soft palate. The device however comprises at least one sensor placed in or near the nares (the nostrils) in order to measure pressure, temperature or the concentration of oxygen. The disclosure however emphatically repeats that the nasal cannulas do not create a seal while the cannulas are in use.
U.S. Pat. No. 4,688,568 discloses a tube for ventilation, which simultaneously obturates (blocks) the esophagus. This tube has two inflatable cuffs, one that is placed in the pharynx, between the soft palate and the back of the tongue. There is however no mention of the measurement of NO, and the disclosure makes it clear that this is a device intended for emergency cases. Further, the disclosure is entirely silent on the possibility to regulate the airflow through the nasal airways, for example by opening and closing the pharyngeal cuff.
The cited exhaled-air collectors and devices are not suited for the determination of exhaled NO in infants and small children up to 6 years old, and also not suited for unconscious, demented or otherwise disabled adults, since these collectors either require an active cooperation of the patient, or fail to isolate the nasal airways, and are frequently uncomfortable to use. Thus, infants, small children or disabled adults are not capable of carrying out the necessary respiratory maneuvers independently and correctly.
Therefore, methods supplementing the ATS/ERS guidelines have been developed for infants and small children that can not cooperate. These methods are however all burdened with disadvantages.
At least one modified form of the “single-breath” method can be used with children older than 2 years old, in which method the regulation of flow takes place by an expiratory resistance that can be manually adjusted. The measuring of NO takes place online during normal spontaneous respiration.
However, as a rule in these methods, the maintaining of an exhalation parameter, usually the regulation of the flow, must be eliminated in order achieve at least the sufficient expiratory pressure in the buccal cavity. One way of guaranteeing the closure of the soft palate in a child, is for example that the child is allowed to blow into a balloon.
One particular problem associated with taking samples of exhaled air from infants and small children, is that they practically exclusively breathe in and out through the nose. Methods that make a permanent closure of the nose necessary can therefore not be used, as they would not be tolerated.
In order to prevent exhalation via the nose, one method prescribes shifting a face mask that covers the mouth and nose down during the exhalation so that the nose wings are compressed from the outside by the mask. The exhalation takes place into a collecting container. The entire apparatus comprises an expiratory resistance of 2 cm H2O that is slightly reduced in comparison to the ATS/ERS guidelines in order prevent a contamination by nasal NO.
Another “single-breath” method modified for infants operates with the artificial compression of the thorax and of the abdomen with the aid of a jacket that can be inflated and deflated with pressurized air, thereby exerting pressure on the thorax and abdomen. The passive exhalation takes place via a face mask against a resistance and at a constant expiratory flow of 50 ml/s. This method has a significant disadvantage in that the infants must be sedated during the procedure.
The invention therefore aims at making available devices and a system for collecting samples of exhaled air, for the purpose of diagnosing the lung function of uncooperative patients, such as infants and small children, and/or disabled, elderly and unconscious patients. The invention relates in particular to the determination of one or more component(-s) in exhaled air, for example, but not limited to nitric oxide (NO) in the exhaled air, aiming at making available a method with which the samples of exhaled air can be taken under normal respiratory conditions and in conformity with the ATS/ERS guidelines. When the component of exhaled air is nitric oxide (NO), contamination of the sample of exhaled air with nasal NO should be avoided to the extent possible.